On the role of the corticotropin-releasing hormone signalling system in the aetiology of inflammatory skin disorders

Abstract

Corticotropin‐releasing hormone (CRH; previously known as corticotropin‐releasing factor) is the central regulator of the hypothalamic–pituitary–adrenal (HPA) axis, which is the main organizer of the body’s response to stress.1–5 Stress induces the hypothalamic production and release of CRH, which then causes the activation of the CRH receptor (CRHR) type 1 (CRHR‐1) in the anterior pituitary to stimulate ACTH release, as well as proopiomelanocortin (POMC) expression and processing.1, 2, 6 ACTH stimulates the production and secretion of cortisol (humans) or corticosterone (rodents) by the adrenal cortex. These steroids regulate the body’s response to counteract effects of the stressor and suppress the HPA axis through the negative feedback mechanism. CRH/POMC expression can also be activated by the cytokines interleukin (IL)‐1, IL‐6 and tumour necrosis factor (TNF)‐α, thus involving the immune system in the central regulation of the HPA axis.7 In addition, CRH together with related urocortin (URC) peptides regulates behavioural, autonomic, endocrine, reproductive, cardiovascular, gastrointestinal and metabolic functions both on the central and on the peripheral levels, and CRH has immunosuppressive effects via the HPA axis.6, 8–12 It is also accepted that peripheral CRH and related peptides have predominantly proinflammatory functions,13, 14 and in this way differ from their central immunosuppressive activity.2 However, recent data also suggest that the peripheral CRH may have dual effects: a direct, short‐term proinflammatory function and an indirect, remote anti‐inflammatory function.15–18 In this issue of the BJD Ganceviciene and colleagues19 report that the complete CRH signalling system is overexpressed in acne‐involved skin with a preferential involvement of the sebaceous glands. Furthermore, the authors propose that overactivation of this CRH system can play an important aetiological role in the development of acne vulgaris through stimulation of local inflammatory reactions. This conclusion is in accordance with the published information that CRH and related URCs are widely produced by human skin in cell type‐ and anatomical region‐specific manners (reviewed15, 20, 21). Furthermore, this expression is regulated by environmental stressors that include ultraviolet radiation and bacterial antigens.15, 22, 23 The expression is also modified by intrinsic factors such as glucocorticoids or the phase of the hair cycle (reviewed21). Skin cells of both epidermal and dermal compartments also express the functional CRHRs type 1 and 2 (CRHR‐1 and CRHR‐2), with CRHR‐1 being the predominant (if not the sole) CRHR type detected in human epidermis (keratinocytes and melanocytes).15, 24 However, CRHR‐2, in addition to CRHR‐1, is expressed in dermal cells including hair follicle keratinocytes, melanocytes and follicular papilla fibroblasts, sebaceous and eccrine glands, muscle and dermal blood vessels.15, 24–27 Both receptors belong to the group II subfamily of G protein‐coupled receptors.6 CRHR‐1 binds CRH and URC1 with high affinity but does not bind URC2. CRHR‐2 shows preferential activation after binding URC2/3, and also binds CRH although with lower affinity than CRHR‐1. The human CRHR1 gene encodes 14 exons and can generate at least seven alternatively spliced isoforms, of which CRHR1α is the most important.6, 8, 15, 28 The CRHR2 gene contains 15 exons and generates several alternatively spliced isoforms with the major forms represented by CRHR2α, β and γ, and with a possibility of generating additional forms because of multiple promoters with intra‐intronic location.6, 21, 29, 30 Coupling of different CRHR‐1/2 isoforms to different signal transduction systems or their functional assignments represents a major challenge in this field, which, however, could provide mechanistic explanations for organ‐ and cell type‐dependent variability of phenotypic responses to the ligand.6, 15, 28 In skin cells, CRH and related peptides exhibit nonendocrine activities regulating cell proliferation, viability, differentiation, secretory and immune activities, thereby defining these peptides as novel important growth factors/pleiotropic cytokines.15, 27, 31–35 Interestingly, there is a skin compartment‐ and cell type‐dependent variability of phenotypic responses to CRH or URCs.15, 24, 25, 31 These are sometimes opposite for different cell types (e.g. keratinocytes vs. fibroblasts)31 or for the same cell type but at a different location (e.g. epidermal vs. follicular melanocytes).25, 31 These phenotypic effects of CRH and related peptides are secondary to modulation of the intracellular concentrations of cAMP, IP3, Ca2+or NF‐κB activity (reviewed15). We have proposed that the net effect of this diverse CRH/URC‐led signalling system(s) is to regulate protective and homeostatic functions of the skin (Fig. 1). Corticotropin‐releasing hormone (CRH)/urocortin (URC) signalling system regulates protective and homeostatic functions of the